1. Field of the Invention
This invention relates to triazole derivatives useful in the treatment of HIV infections and the method of their use. These compounds are useful for treating retrovirus-associated cancer, and modulating reverse transcriptase, RNase, HIV polymerase.
2. Related Background Art
The retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system and degeneration of the central and peripheral nervous system (acquired immune deficiency syndrome; AIDS). A common feature of retrovirus replication is reverse transcription of the RNA genome by a virally encoded reverse transcriptase. Reverse transcriptase is implicated in the infectious lifecycle of HIV, and compounds such as nucleoside and non-nucleoside reverse transcriptase inhibitors, which interfere with the function of this enzyme, have shown utility in the treatment of conditions including AIDS.
Presently, there are four categories of drugs used to treat HIV infection, which include nucleoside analogue reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Reverse transcriptase inhibitors, including the nucleoside and non-nucleoside categories, interfere with HIV reverse transcriptase, which, as noted above, is required for viral replication. Protease inhibitors interfere with the enzyme protease, which plays a major role in viral infection. Forms of anti-HIV therapy include giving only one reverse transcriptase inhibitor at a time (monotherapy), a combination of two or more reverse transcriptase inhibitors (combination therapy), and a combination of reverse transcriptase inhibitors and protease inhibitors (combination therapy with protease inhibitors). Nucleoside analogues include AZT (zidovudine, Retrovir), ddI (didanosine, Videx), 3TC (lamivudine, Epivir), d4T (stavudine, Zerit), abacavir (Ziagen) and ddC (zalcitabine, Hivid). AZT and 3TC are also available in a single combined pill called Combivir and AZT, 3TC and abacavir are available in a single combined pill called Trizivir. Tenofovir (Viread), a nucleotide analogue, is the only nucleotide analogue currently available for prescription and is only licensed to give people on their second or later treatment combination, although it may be given to people in their first-line treatment. Nucleotide analogues are very similar to nucleoside analogues. The only difference is that nucleotide analogues, unlike nucleoside analogues, are chemically preactivated and thus require less processing in the body for them to become active. Non-nucleoside reverse transcriptase inhibitors include Sustiva, nevirapine (Viramune), and delavirdine (Rescriptor).
Many of the treatments which inhibit reverse transcriptase activity that are currently available, particularly the nucleoside analogues, are associated with serious side effects and require long term treatment to be effective. In addition, the virus is able to mutate in response to the drugs and becomes resistant to them. Therefore, there is a constant need to provide new and better treatments for HIV and AIDS and particularly new drugs that inhibit HIV reverse transcriptase.
Triazole derivatives are known for their usefulness as insecticides, fugicides, mircobicicles and plant growth regulators. Triazole compounds have also been found useful as hydrophobic textile dyes and as therapeutic agents.
In U.S. Pat. Nos. 4,742,072 and 4,291,043, it is disclosed that triazole compounds are useful as insecticides, molluscicides and plant growth regulating agents without toxicity to humans and animals.
In the following U.S. patents, triazole derivates are disclosed and their plant fugicide activity is discussed: U.S. Pat. Nos. 3,937,713, 4,082,762 and 4,120,864.
In the following U.S. patents, Triazole derivatives are shown to possess microbicide activity: U.S. Pat. Nos. 6,274,610, 6,166,059, 6,080,775, 5,859,039, 5,789,430 and 5,496,793.
Triazole derivatives have also been shown to be useful as therapeutic agents. In U.S. Pat. No. 5,260,450, triazole compounds are described as useful in treating muscle tension, muscle spasms, the associated pain, hyperreflexia, convulsant seizures and anxiety. Triazole compounds have been described as selective dopamine-D3-receptor inhibitors useful for mediating the effects of antipyschotics and anti-Parkinson agents in U.S. Pat. Nos. 6,583,166 and 6,579,892. U.S. Pat. No. 5,508,419 discloses triazole compounds that are angiotensen II receptor antagonists, which are useful in the treatment of hypertension, congestive heart failure, elevated ocular pressure, cerebral stroke, angina, cardiac insufficiency, myocardial infraction and diabetic nephropathy.